Dal Canto M C
Northwestern University Medical School, Chicago, IL, USA.
Clin Neurosci. 1995;3(6):332-7.
The first part of this paper summarizes the main pathological features of sporadic amyotrophic lateral sclerosis (ALS) and familial amyotrophic lateral sclerosis (FALS). In both diseases, the primary lesion consists of degeneration of both upper and lower motor neurons, resulting in severe neuronal loss, particularly in the spinal cord. An important difference between sporadic ALS and FALS is in the involvement of sensory and spinocerebellar projections in the latter. The second part of the paper will compare the familial form of ALS with its recently described transgenic murine model. The production of this model followed the discovery that FALS is tightly linked to several different mutations in the enzyme Cu,Zn superoxide dismutase (SOD), a ubiquitous enzyme involved in the dismutation of superoxide anion to hydrogen peroxide. A human transgene with one of the identified mutations was expressed in mice, and the resulting progeny developed clinical and pathological changes that, in the late stages of disease, were very similar to those in patients with FALS. There was, in fact, exquisite degeneration of motor neurons in spinal cord and brain stem, as well as degeneration of white matter tracts of the spinal cord, of the anterior roots and neurogenic atrophy of skeletal muscles, as described in patients with FALS. Beckman and colleagues postulated that mutations in SOD may alter the structure of the copper active site with resultant decrease in superoxide anion dysmutation while favoring an increase in reactivity with other radicals such as peroxynitrite. The formation of nitronium-like intermediate could damage proteins, particularly by nitration of tyrosine residues. Nitration of tyrosine kinases and altered phosphorilation of neurofilaments could be particularly damaging for motor neurons.
本文的第一部分总结了散发性肌萎缩侧索硬化症（ALS）和家族性肌萎缩侧索硬化症（FALS）的主要病理特征。在这两种疾病中，主要病变均包括上下运动神经元的变性，导致严重的神经元丧失，尤其是在脊髓中。散发性ALS和FALS之间的一个重要区别在于后者存在感觉和脊髓小脑投射受累的情况。本文的第二部分将比较家族性ALS与其最近描述的转基因小鼠模型。该模型的构建是在发现FALS与酶铜锌超氧化物歧化酶（SOD）的几种不同突变紧密相关之后进行的，SOD是一种普遍存在的酶，参与将超氧阴离子歧化为过氧化氢的过程。将带有其中一个已鉴定突变的人类转基因在小鼠中表达，所产生的后代出现了临床和病理变化，在疾病后期与FALS患者的变化非常相似。实际上，正如FALS患者中所描述的那样，脊髓和脑干中的运动神经元出现了严重变性，同时脊髓白质束、前根也发生了变性，骨骼肌出现了神经源性萎缩。贝克曼及其同事推测，SOD中的突变可能会改变铜活性位点的结构，从而导致超氧阴离子歧化作用减弱，同时增加与其他自由基（如过氧亚硝酸盐）的反应性。硝鎓样中间体的形成可能会损害蛋白质，特别是通过酪氨酸残基的硝化作用。酪氨酸激酶的硝化和神经丝磷酸化的改变可能对运动神经元造成特别大的损害。
